Various publications or patents are referred to throughout this application to describe the state of the art to which the present invention pertains. Each of these publications or patents is incorporated by reference herein.
Angiogenesis, simply defined as the growth of new blood vessels, is an important natural process occurring in the body, both in health and in disease. Angiogenesis is controlled through a series of “on” and “off” switches. The main “on” switches are known as angiogenesis-stimulating growth factors and the main “off” switches are known as angiogenesis inhibitors. When angiogenic growth factors are produced in excess of angiogenesis inhibitors, the balance is tipped in favor of blood vessel growth. When inhibitors are present in excess of stimulators, angiogenesis is stopped. The normal healthy body maintains a balance of angiogenesis modulators (Risau, W., Nature 1997, 386: 671-74) The process of angiogenesis follows an orderly sequence of events. Diseased or injured tissues produce and release angiogenic growth factors, which are proteins or polypeptides that participate in the process of new blood vessel formation. The angiogenic growth factors bind to specific receptors located on the endothelial cells nearby preexisting blood vessels. Once growth factors bind to their receptors, the endothelial cells become activated. Signals are sent from the cell's surface to the nucleus. The endothelial cell's machinery begins to produce new molecules and enzymes. The enzymes dissolve tiny holes in the sheath-like covering (basement membrane) surrounding all existing blood vessels and the endothelial cells begin to proliferate, as they migrate out through the dissolved holes of the existing vessel towards the diseased tissue. Specialized molecules, called adhesion molecules or integrins serve as grappling hooks to help pull the sprouting new blood vessel forward. Matrix metalloproteinases are produced to dissolve the tissue in front of the sprouting vessel tip in order to accommodate it. As the vessel extends, the tissue is remolded around the vessel. Sprouting endothelial cells roll up to form blood vessel tube and individual blood vessel tubes connect to form blood vessel loops that can circulate blood. Finally, newly formed blood vessel tubes are stabilized by pericytes, specialized smooth muscle cells that provide structural support. Blood flow then begins.
In the healthy body, angiogenesis may occur to heal wounds or to restore blood flow to tissues after injury or insult. In females, angiogenesis occurs during the monthly reproductive cycle, to rebuild the uterus lining or to mature the egg during ovulation, and during pregnancy, to build the placenta, the circulation between mother and fetus. In many serious disease states, however, the body loses control over angiogenesis. Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently. Excessive angiogenesis occurs in diseases such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, and more than 70 other conditions. In these conditions, new blood vessels feed diseased tissue, destroy normal tissues, and in the case of cancer, the new vessels nourish tumor cells with oxygen and nutrients and allow tumor cells to escape into the circulation and lodge in other organs. Angiogenesis contributes to both the invasiveness of tumor cells and to their ability to metastasize to distant sites, the two major causes of the lethality of cancer, which kills over half a million patients each year in the United States.
On the other hand, insufficient angiogenesis occurs in diseases such as coronary artery disease, stroke, and delayed wound healing. In these conditions, inadequate blood vessels grow and circulation is not properly restored, leading to the risk of tissue death. Promotion of angiogenesis in wound healing would aid in the healing of broken bones, burns, diabetic ulcers, or traumatic or surgical wounds, and organ transplantation. Pro-angiogenic drugs may also be used to treat peripheral vascular disease, cerebral vascular disease, hypoxic tissue damage, or coronary vascular disease as well as to treat patients who have or have had transient ischemic attacks, vascular graft surgery, balloon angioplasty, frostbite, gangrene, or poor circulation.
Because dysregulated angiogenesis is the root cause of the pathophysiology of a significant number of diseases, identifying the factors responsible for the up- or downregulation of angiogenesis and designing strategies to modulate their activity has become an urgent clinical priority. As such, the identification of a novel potent angiogenic stimulator and the ability to modulate its activity thus represent a major advance in the art of pro-angiogenic therapeutics. Likewise, the identification of a novel potent angiogenic regulator capable of specifically inducing endothelial cell apoptosis and the ability to modulate its activity thus represent a major advance in the art of anti-angiogenic therapeutics.